RADIATION THERAPY FOR EARLY STAGE HODGKIN’S LYMPHOMA

CURRENT CONSENSUS

DR. SANDIP SARKAR FELLOW, TMC

Vera Peters (1950): The first physician to present definitive

evidence of curability of Hodgkin’s disease.

Reviewed the records 113 patients treated at the Ontario

Institute of Radiotherapy from 1924 – 1942 and reported 10

year survival rates of 79% for stage I Hodgkin’s disease using

high dose fractionated extended field radiation therapy

Am J Roentgenol 1950; 63: 299-311.

1960’sDevelopment of the MOPP regimenAppreciation of adverse effects of “High Dose Radiation”Investigation of “Combined Modality Therapy”

1970’s & 80’sDevelopment of better imaging facilities (CT scan)Diminished importance of staging laparotomy

GHSG HD 78 – all pts lap stagedGHSG HD 82 – all lap staged, splenectomy only if visible

abnormalities at lapGHSG HD 85 – lap staging only if abnormal USG/ CT scanGHSG HD 90 – laparotomy abandoned

Risks of Infertility / Leukemogenesis – Alkylating agentsDevelopment of ABVD regimenDevelopment of MOPP/ ABVD hybrid regimenReduction in doses of radiotherapy when used with chemo

IMROVEMENT IN SURVIVAL

COTSWALDS MODIFICATION OF ANN ARBOR STAGING

The 90’s

Recognition of the need to optimize therapy (Chemo & RT)

Recognition of prognostic groupsEarly Stage FavourableEarly Stage Unfavourable

Development of risk adapted therapy

RISK FACTORS & TREATMENT GROUPS

Early Stage Risk Factor Treatment Group

EORTC Bulky Mediast. MassAge ≥ 50 yrsElevated ESRB Symptoms≥ 4 nodal regions

Fav: St. I-II without risk factorsUnfav: St. I-II with risk factors

GHSG Bulky Medist. MassElevated ESRB Symptoms≥ 3 nodal regions

Fav: St. I-II without risk factorsIntermed: St. I-IIA with risk factorsUnfav: St. IIB with Elevated ESR

ECOG & NCI-C Histology (MC, LD)Age ≥ 40 yrsElevated ESRB Symptoms≥ 4 nodal regions

Fav: St. I-II without risk factorsUnfav: St. I-II with risk factors

LYMPH NODAL REGIONS

CAN WE AVOID CHEMOTHERAPY FOR EARLY STAGE

FAVOURABLE DISEASE ?

JCO August 2007

RT Alone: 67%CTh + RT: 88%

RT vs. CT + RT FOR EARLY STAGE FAVOURABLE HD

Trial Treatment Outcome OS

EORTC H7STNI (36-40Gy)6 EBVP+IFRT (36-40Gy)

10 yr EFS78%88%

10 yr92%92%

SWOG 9133STNI (36-40Gy)3 x Dox + Vinblast + STNI

3 yr EFS8194

3 yr9698

EORTC/ GELA H8 STNI 36Gy (IF 40Gy)

3 x MOPP/ ABV + IFRT (36Gy)

4 yr FFTF7799

4 yr9599

COMBINED MODALITY

13 randomized clinical trialsMultiagent CT+RT VsRadiation alone

At 10 years RFSR 85% and 67% p=0.00001 10-year OAS 79% and 76%

(p=0.07).

Diehl V.. J Cancer Res Clin Oncol 1990.

Metaanalysis

3 Year EFS CTh Alone: 85%3 Year EFS CTh + RT: 93%, p=0.0024

WHAT IS THE OPTIMAL RADIATION VOLUME ?

MANTLE FIELD FOR TREATMENT OFSUPRADIAPHRAGMATIC NODAL REGIONS

RT DOSE: 15-30Gy

INVERTED “Y” FIELDFOR TREATMENT OF

INFRADIPHRAGMATICNODAL REGIONS

INRT (Involved Nodal RT)

IFRT

Mini Mantle

Mantle

Modified Mantle

Inverted “Y”

Subtotal Nodal Irradiation

Total Nodal Irradiation

CT + RT FOR EARLY STAGE FAV. HD

Trial Treatment Outcome OS

Milan Group4 ABVD + STNI 30Gy (36-40Gy)4 ABVD + IFRT (36-40Gy)

12 yr EFS87%91%

12 yr96%94%

GHSG HD 102 ABVD + IFRT 30Gy 2 ABVD + IFRT 20Gy 2 ABVD + IFRT 30Gy 2 ABVD + IFRT 20Gy

2 yr EFS 96.6% 2 yr 98.5%

EORTC/ GELA H9F 6 EBVP + IFRT 36Gy

6 EBVP + IFRT 20Gy6 EBVP

4 yr FFTF87%84%70%

4 yr98%98%98%

Trial Treatment Outcome OS

EORTC-GELA H8-U 6 MOPP/ABV + IFRT (36-40Gy)

4 MOPP/ABV + IFRT (36-40Gy)4 MOPP/ABV + STNI (36-40Gy)

4 yr TFFS89%92%92%

4 yr90%94% 92%

GHSG HD 82 COPP/ABVD + EFRT 30Gy2 COPP/ABVD + IFRT 30Gy

% yr FFTF86%84%

5 yr 9192

EORTC-GELA H9U 6 EBVP + IFRT 36Gy

6 MOPP/ABV + IFRT 36Gy

10yr EFS68%88%

10 yr79%87%

GHSG HD-114 ABVD + IFRT 30Gy4 ABVD + IFRT 20Gy4BEACOPP + IFRT 30Gy4 BEACOPP + IFRT 20Gy

FFTF 89.9% OS 97.4%

CT + RT FOR EARLY STAGE UNFAV. HD

Reduction in field sizes

8 randomized controlled trialsExtensive portals (e.g. subtotal

mantle, total nodal irradiation etc)

Vs less extensive portals (e.g.

mantle, mini mantle, involved field radiation etc).

Results –• At 10 years, the risk of recurrence

was 31% vs. 43% ( p=0.00001).• Subgroup analysis showed similar

results. • 10-year actuarial OAS- 77% in both

groups (p=0.1)

Metaanalysis BY Specht 1998

WHAT IS THE OPTIMAL RADIATION DOSE ?

RADIATION DOSE

HD-10 trial

1131 patients (1998-2002)

Randomized into 4 arms: a) ABVD x 2 + (30Gy) b) ABVD x 2 + IFRT (20Gy) c) ABVD x 4 + IFRT (30Gy) d) ABVD x 4 + IFRT (30Gy).

• Results: interim analysis conducted in August 2003 of 847 pts (75%)

• Complete remission rates-98.4%

• FFTF after two years – 96.6% with no statistical differences between arms

• Overall survival- 98.5% without any statistical differences in CT and RT comparisons.

JCO July 2007

IJROBP 2003

IJROBP 2001

HODGKIN’S DISEASE CURRENT GUIDELINES

Early Stage Favourable (Low Risk)Multiagent CTh x 2 - 4 cycles + IFRT

Early Stage Unfavourable (Intermediate Risk)Multiagent CTh x 4 cycles + IFRT

Advanced Stage (High Risk)Multiagent CTh x 6-8 cycles ± IFRT

INDICATIONS FOR ADJUVANT RADIATION THERAPY

Bulky Disease at Presentation (Irrespective of Response to CT)

Residual Disease/ Partial Response after Chemotherapy

WITHIN CLINICAL TRIAL

Adults: Microscopic: 19.8Gy/11#/3wks @ 1.8Gy / fr.Gross: 30.6Gy/17#/3wks @ 1.8Gy / fr

Paediatric: Microscopic: 14.4Gy/8#/2wks @ 1.8Gy / fr.Gross: 25.2Gy/14#/3wks @ 1.8Gy / f

RADIATION DOSE GUIDELINES IN TMC

OUTSIDE CLINICAL TRIAL

Adults: Microscopic: 25.2Gy/14#/3wks @ 1.8Gy/fr.Gross: 34.2Gy/19#/4wks @ 1.8Gy/fr. Paediatric: Microscopic: 19.80Gy/11#/3wks @ 1.8Gy/fr.Gross: 30.60Gy/17#/3wks @ 1.8Gy/fr.

Definition of IFRT (ASTRO 2002)

• IFRT encompasses a region, not an individual LN

• Initially involved pre-chemo sites and volume are treated except transverse diameter of mediastinum and paraaortic LN for which reduced post chemo vol is treated

Major involved field region are: • Neck: Ipsilateral cervical and SCV

Cont…

• Mediastinum: Include B/L hilar region , if SCV involved then B/L SCV and cervical region

• Axilla: Include ipsilateral SCV and infraclavicular region

• Inguinal: Include ext iliac and femoral regions.

BASIC RULES

• Examination of patient by Radiation Oncologist.

• Pre and Post chemotherapy CT and FDG-PET scan performed in the treatment position.

• Scans should encompass cervical, axillary, and mediastinal areas.

• Remission status – For each initially involved lymph node should be determined exclusively on CT scans.

• Modern Radiation techniques

- Immobilization. - CT simulation. - Fusion techniques. - 3D-CRT. - Intensity modulated Radiotherapy. - Respiratory Gated Radiotherapy.

Initially involved lymph nodes in PR (Partial Remission)

CERVICAL AND AXILLARY LYMPH NODES

• GTV - The lymph node remnant(s).

• CTV - The initial volume of the lymph node(s) before chemotherapy.

• PTV1 - The CTV including the GTV [i.e. initial tumor mass and lymph node remnant(s)] with a

margin.

• PTV2 - The GTV alone with a margin.

MEDIASTINAL AREA

• GTV - Lymph node remnant(s) or the remaining mass alone.

• CTV - The initial volume of the mediastinal mass.

• PTV1 - The CTV including the GTV (i.e. the initial tumor mass and the lymph node remnant(s) with a margin.

• PTV2 - The GTV alone with a margin.

TREATMENT AND DOSE PRESCRIPTION

PTV1 – 30 GY

PTV2 – 6 GY

HODGKIN’S DISEASEABVD X 6 Cycles ------- Relapsed Salvage MINE X 2 cycles

Progressive Disease + Chest Wall Nodule

TOMOTHERAPY DVH

PTV Dose

Tomotherapy Con. IMRT

V95 % 99.44% 69%

V99% 98.44% 53%

V107% 0.1% 15%

LATE CAUSES OF DEATHIN HODGKIN’S DISEASE

STANFORD

JCRT

IDHD

LATE EFFECTS OF HODGKIN’S DISEASE TREATMENT

Musculoskeletal abnormalities

Pulmonary Sequelae

Cardiovascular Sequelae

Thyroid dysfunction

Second MalignanciesLeukemogenesisNHLSolid Tumors

GROWTH, HEIGHT, MUSCULOSKELETAL EFFECTS

Factors Influencing Growth

• Chronological age at treatment• RT volume• Total RT dose• RT dose per fraction• Site of treatment• Homogeneity of growth plate irradiated• Surgery• Chemotherapy

S Donaldson , 1992

RELATIVE LOSS OF ADULT HEIGHT

• 7.7% (13cm) with RT dose > 33Gy, Entire spine (pre-pubertal age)• No clinically significant loss of height with low dose RT • IFRT associated with clinically insignificant height loss• No disproportion between sitting & standing height

William KY, IJROBP 1993;28:85Stanford

CARDIOVASCULAR LATE EFFECTS

STANFORD(1960-1995)

2498 Pts. 754 Deaths 16% CV disease

JCRT(1969-1996)

794 Pts. 124 Deaths 14%CV disease

EORTC(1963-1986)

1449 Pts. 240 Deaths 7%CV disease

BNLI 1043 Pts. 43 Deaths 14%CV disease

Decreasing CV deaths with improving therapy (CT & RT)

Stage I & II at Stanford (CV deaths after 15yrs of treatment)1962 - 1980: 812 pts. ------ 5.4%1980 – 1996: 628 pts. ------ 0.8%

TYPE/ SITE RELATIVE RISK ABSOLUTE RISK /10,000 pts,Per Yr.

RELATIVE RISKIn 10yr survivor

ABSOLUTE RISK In 10yr survivor Per 10,000 pts,Per Yr.

All cancers 3.5 (3.1 – 3.8) 56.2 4.7 (3.8 – 5.7) 111.7

Leukemia 32.4 (25.5 – 40.6)

16.8 16.2 (6.5 – 33.3)

9.9

NHL 18.6 (13.8 – 24.6)

10.7 32.7 (19.7 – 51.1)

27.8

Solid tumors Female breast Lung

2.4 (2.1 – 2.7)2.5 (1.8 – 3.4)4.2 (3.3 – 5.2)

29.3 11.3 13.5

3.6 (2.8 – 4.6)4.6 (3.0 – 6.6)7.3 (4.7 – 10.6)

74.439.533.8

RISK OF SECOND CANCERS

Van Leeuwen FE, J Clin Oncol 1994;12:312Swerdlow AJ, Br Med J 1992;304:1137Tucker MA, NEJM 1988;318:76

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